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Abstract: Leptin has been suggested to mediate a variety of actions, including bone development, via its ubiquitously expressed receptor (Ob-Rb). In this study, we investigated the role of leptin in endochondral ossification at the growth plate. The growth plates of wild-type and ob/ob mice were analyzed. Effects of leptin on chondrocyte gene expression, cell cycle, apoptosis and matrix mineralization were assessed using primary chondrocyte culture and the ATDC5 cell differentiation culture system. Immunohistochemistry and in situ hybridization showed that leptin was localized in prehypertrophic chondrocytes in normal mice and that Ob-Rb was localized in hypertrophic chondrocytes in normal and ob/ob mice. Growth plates of ob/ob mice were more fragile than those of wild-type mice in a mechanical test and were broken easily at the chondro-osseous junction. The growth plates of ob/ob mice showed disturbed columnar structure, decreased type X collagen expression, less organized collagen fibril arrangement, increased apoptosis and premature mineralization. Leptin administration in ob/ob mice led to an increase in femoral and humeral lengths and decrease in the proportional length of the calcified hypertrophic zone to the whole hypertrophic zone. In primary chondrocyte culture, the matrix mineralization in ob/ob chondrocytes was stronger than that of wild-type mice; this mineralization in both types of mice was abolished by the addition of exogenous leptin (10 ng/ml). During ATDC5 cell differentiation culture, exogenous leptin at a concentration of 1–10 ng/ml (equivalent to the normal serum concentration of leptin) altered type X collagen mRNA expression and suppressed apoptosis, cell growth and matrix calcification. In conclusion, we demonstrated that leptin modulates several events associated with terminal differentiation of chondrocytes. Our finding that the growth plates of ob/ob mice were fragile implies a disturbance in the differentiation/maturation process of growth plates due to depletion of leptin signaling in ob/ob mice. These findings suggest that peripheral leptin signaling plays an essential role in endochondral ossification at the growth plate. [Copyright &y& Elsevier]

The purpose of this investigation is to evaluate the diagnostic ability of three-dimensional spoiled gradient-echo (3D SPGR) magnetic resonance (MR) imaging in cases of osteonecrosis of the femoral head (ONFH), and to determine the accuracy of 3D SPGR imaging in area and volume measurement of ONFH. T1-weighted spin-echo (SE) and 3D SPGR imaging were performed on 20 femoral heads obtained from patients with ONFH. After MR imaging, the femoral heads were cut parallel to the imaging plane and were evaluated histologically. Areas and volumes of necrotic lesions were measured with a computer program and the deviation between MR images and anatomical measurements was evaluated. A low signal intensity band on 3D SPGR MR images was observed in all femoral heads and corresponded histologically to repaired marrow with viable fibrous mesenchymal tissue. The area proximate to the low band area coincided with the necrotic region. Both area and volume measurements by T1-weighted SE and 3D SPGR images showed a strong correlation to histological measurements. The discrepancies between histological and imaging results were minimal in 3D SPGR imaging, especially at the anterior and posterior portions of the femoral head. Three-dimensional SPGR imaging provides more accurate measurements of the area and volume of a necrotic lesion than T1-weighted SE imaging. [Copyright &y& Elsevier]

When a neutral solution of thymidine and ascorbic acid was irradiated with UV light of wavelength longer than 300 nm in the presence of salicylic acid as a photosensitizer, six product peaks appeared in an HPLC chromatogram in addition to small amounts of thymidine dimers. The six products were identified as three pairs of diastereomers of 5-(2-deoxy-2- l -ascorbyl)-5,6-dihydrothymidine, 5-(2- l -ascorbyl)-5,6-dihydrothymidine, and 5,6-dihydrothymidine. These results suggest that novel DNA damage may be generated by ascorbic acid with salicylic acid induced by sunlight. [ABSTRACT FROM AUTHOR]

Previous studies have reported that continuous infusion with substance P (SP) into rat dorsal striatum ameliorated both mechanical allodynia in both formalin-evoked transient inflammatory pain and neuropathic pain models. However, a role of striatal SP in persistent inflammatory pain has not been demonstrated. The current study examined the effect of continuous infusion of SP into the rat dorsal striatum by reverse microdialysis on persistent inflammatory pain induced by complete Freund's adjuvant (CFA). Intraplantar injection of CFA evoked both mechanical allodynia and paw edema 3 and 7 days post-injection. The continuous infusion of SP ameliorated the CFA-evoked mechanical allodynia, but not paw edema, 3 days after the CFA injection. This antinociceptive effect of SP was partially inhibited by co-infusion with the neurokinin-1 (NK1) receptor antagonist CP96345. Conversely, at 7 days both CFA-evoked mechanical allodynia and paw edema were not affected by SP treatment. To clarify why the effect of SP treatment on CFA-induced pain changed, we evaluated NK1 receptor protein levels at both time points. The NK1 receptor protein level was decreased at 7, but not 3, days post CFA injection. These data suggest that persistent inflammatory pain can downregulate the striatal NK1 receptor. The current study demonstrates that striatal SP-NK1 receptor pathway can exert antinociceptive effect only on the third days of inflammatory pain phase defined as an acute but not the 7 days defined as a subacute. • Substance P infusion into the striatum attenuates acute inflammatory pain. • Antinociceptive effects of Substance P can be blocked by an NK1 receptor antagonist. • Substance P treatment shows no antinociceptive effect in the subacute phase. • Substance P treatment does not affect complete Freund's adjuvant-induced paw edema. • Striatal NK1 receptor is downregulated in the subacute phase. [ABSTRACT FROM AUTHOR]

Background: Alternative medicine is noted for its clinical effect and minimal invasiveness in the treatment of neuropathic pain. Go-sha-jinki-Gan, a traditional Japanese herbal medicine, has been used for meralgia and numbness in elderly patients. However, the exact mechanism of GJG is unclear. This study aimed to investigate the molecular mechanism of the analgesic effect of GJG in a chronic constriction injury model. Results: GJG significantly reduced allodynia and hyperalgesia from the early phase (von Frey test, p < 0.0001; cold-plate test, p < 0.0001; hot-plate test p = 0.011; two-way repeated measures ANOVA). Immunohistochemistry and Western blot analysis revealed that GJG decreased the expression of Iba1 and tumor necrosis factor-α in the spinal cord. Double staining immunohistochemistry showed that most of the tumor necrosis factor-α was co-expressed in Iba1-positive cells at day 3 post-operation. GJG decreased the phosphorylation of p38 in the ipsilateral dorsal horn. Moreover, intrathecal injection of tumor necrosis factor-α opposed the anti-allodynic effect of GJG in the cold-plate test. Conclusions: Our data suggest that GJG ameliorates allodynia in chronic constriction injury model mice via suppression of tumor necrosis factor-α expression derived from activated microglia. GJG is a promising drug for the treatment of neuropathic pain induced by neuro-inflammation. [ABSTRACT FROM AUTHOR]

Objectives: It has been reported that postherpetic neuralgia (PHN) in patients over 60 years of age is aggravated under cold stimulation and is often difficult to treat. Keishikajutsubuto (TJ-18) and Bushi-matsu (TJ-3022) are traditional Japanese herbal medicines and have long been used to treat neuralgia and arthralgia, which are aggravated following cold stimulation. This study was designed to evaluate the effectiveness of combined TJ-18 and TJ-3022 therapy in cases of PHN aggravated by self-reported cold stimulation. Design: Fifteen (15) PHN patients aged 60 years and over were examined. Patients were aware of the persistent pain despite other treatments; pain was generally aggravated following exposure to cold stimulation. First, TJ-18 (7.5 g/day) was administered to patients, and then TJ-3022 (1.0 g/day) was also administered and progressively increased by 0.5-1.0 g increments every 2-4 weeks, until stable improvement was achieved, which was rated using the visual analogue scale (VAS). Analgesic effects were evaluated using the VAS during each patient visit. Outcome measures: Background variables, responses to treatment (time course of VAS rating, VAS improvement rate), the amount of additional TJ-3022 administered, and adverse reactions were analyzed. Results: Twelve (12) of the 15 patients completed the entire trial. Patient ages were 61-85 years, the male-to-female ratio was 4:8, and length of time after onset of herpes zoster was 2-92 months. In 3 patients, oral TJ-18 treatment was not possible due to hot flash or gastric discomfort. The VAS improvement rate for patients being orally administered both TJ-18 and TJ-3022 was 76.5±27.7% (mean±standard deviation). The additional TJ-3022 dose was 1.0-5.0 g/day. Twelve (12) patients have been treated without serious adverse reactions. Conclusions: TJ-18 and TJ-3022 combination treatment is a promising means of treating intractable PHN, which has a self-reported tendency to aggravate pain under cold stimulation. [ABSTRACT FROM AUTHOR]

Little is known about scintigraphic image patterns in the various stages of coxarthrosis. We assessed bone scintigraphy in 159 patients (210 hips) with dysplastic arthrosis of the hip. Scintigraphic images were divided into 5 types related to the radiographic stages of the disease. The scintigraphic images showed little, if any, uptake in the stage of prearthrosis. In the early stage, we found an increase in uptake in the weight bearing area in 30% of cases. In the advanced stage, more than half of the cases had an increase in uptake in the medial side of the joint and in the weight bearing area. In the terminal stage, a marked increase in uptake in the weight bearing area was commonest. Since the osteoblastic reaction intensified, a marked increase in uptake was seen not only in the weight bearing area, but also throughout the entire joint. These types of scintigraphic patterns, which change with the stage of coxarthrosis, seem to reflect the natural course of the disease. All hips with rapid progression of the disease showed a marked increase in uptake of radionuclide the entire joint at earlier stages. [ABSTRACT FROM AUTHOR]

• Continuous substance P infusion into striatum relieves neuropathic pain. • Continuous enkephalin infusion into striatum is not antinociceptive. • Neurokinin-1 receptor block suppresses the antinociceptive effect of substance P. • Muscarinic receptors are required for the antinociceptive effect of substance P. Previous studies have demonstrated that continuous substance P (SP) infusion into the rat striatum attenuated hind paw formalin-induced nociceptive behaviors and mechanical hypersensitivity via a neurokinin-1 (NK1) receptor dependent mechanism. However, whether there is a role of striatal infusion of SP on chronic, neuropathic pain has yet to be demonstrated. The present study investigated the effect of continuous SP infusion into the rat striatum using a reverse microdialysis method is antinociceptive in a rat model of chronic, mononeuropathic pain. Two weeks after partial sciatic nerve injury, the ipsilateral hind paw demonstrated mechanical hypersensitivity. Infusion of SP (0.2, 0.4, or 0.8 μg/mL, 1 μL/min) for 120 min into the contralateral striatum dose-dependently relieved mechanical hypersensitivity. The antinociceptive effect of SP infusion was inhibited by co-infusion with the NK1 receptor antagonist CP96345 (10 μM). Neither ipsilateral continuous infusion nor acute microinjection of SP (10 ng) into the contralateral striatum was antinociceptive. A role of striatal muscarinic cholinergic neurons is suggested since co-infusion of SP with atropine (10 μM), but not the nicotinic receptor mecamylamine (10 μM), blocked antinociception. The current study suggests that activation of striatal muscarinic receptors through NK1 receptors could be a novel approach to managing chronic pain. [ABSTRACT FROM AUTHOR]